Many types of cancer chemotherapy suffer from severe side effects. New methods for selective delivery of potent cytotoxic agents to cancer cells are needed to solve this problem. Current approaches include targeting a drug to a cancer cell using an antibody, release of a cytotoxic compound from an inactive, prodrug form in the presence of the cancerous cell, and photodynamic therapy, where light is used to create cytotoxic singlet oxygen from an inherently non-toxic photosensitizer. This reliance on photosensitizers has drawbacks; in particular, it means that all photodynamic therapy is dependent on oxygen, a problem in hypoxic tumor microenvironments. The first objective of this proposal is the development of two versatile and oxygen independent strategies for cancer treatment based on light-enabled drug delivery. The first strategy involves attaching a drug to a cell impermeable group via a light-scissile linker. Illumination will release the free drug permitting its entry into the cell. A second strategy involves using a conformationally switchable peptide that becomes cell permeable upon illumination, allowing it to carry the drug across the cell membrane. Although in principle both of these strategies could be used to deliver many types of drugs, this proposal will focus on the anticancer chemotherapeutic doxorubicin. For both strategies, the enhancement in entry of the conjugates into esophageal adenocarcinoma cells will be monitored using flow cytometry and confocal microscopy. The IC50 values of the doxorubicin conjugates in the presence and absence of light will be determined, and spatial control of cell death by light will be established. Cell death in hypoxic environments will also be verified. Finally, the off target-toxicity of the doxorubicin conjugates will be analyzed using cardiomyocytes, bone marrow cells, and fibroblasts. Successful implementation of light-enabled drug delivery will provide a new, powerful approach for light-targeted cancer treatment. PUBLIC HEALTH RELEVANCE: This proposal aims to develop a new versatile method for the treatment of esophageal cancer with light. Light will be used to deliver a chemotherapeutic agent into esophageal cancer cells.